20-keto-17, 21-alkylidenedioxy steroids and processes for their manufacture and transformation



United States Patent 3,116,289 20-KETO-17,2l-ALKYLIDENEDIOXY STEROIDS AND PROCESSES FGR THEIR MANUFAC- TURE AND TRANSFGRMATION Masato Tanahe, Palo Alto, Calif., assignor to chering Corporation, Bloomfield, N.J., a corporation of New Jersey No Drawing. Filed Aug. 21, 1961, Ser. No. 132,543 16 Claims. (Cl. 260-23955) This invention pertains to novel steroidal substances and to methods for their manufacture. More particularly, it relates to the steroids wherein the dihydroxyacetone side chain of a pregnane or unsaturated pregnane is transformed into a 17,2l-alkylidenedioxy function. This application is a continuation-in-part of three earlier filed applications Serial Numbers 845,594, 845,595 and 845,661, all filed on October 12, 1959, said applications now abandoned.

By far, most of the physiologically active steroids are members of the pregnane series possessing a dihydroxyacetone side chain at the C-l7 position. The complete side chain in many instances is a necessary feature in order for the pregnane to possess a particular activity such as evidenced by the adrenocarticoids like cortisone, hydrocortisone, prednisone, prednisolone and the related analogs. It is well known that the dihydroxy acetone side chain is particularly reactive with oxidative, reductive, acidic and basic reagents, necessitating blocking during transformations performed elsewhere in the molecule. I have found that conversion of the dihydroxyacetone side chain present at the C-l7 position of a pregnane or unsaturated pregnane into a 17,21-alkylidenedioxy group provides for effective deactivation of said side chain and offers several other advantages described in further detail below.

It is thus an object of my invention to provide a new series of steroid compounds of the pregnane series possessing a ZO-keto-17,21-alkylidenedioxy group, said group effectively providing protection to the side chain during chemical transformation elsewhere in the molecule. It is an object of my invention to provide a method for preparing these new compounds and also provide a method for regenerating the dihydroxy side chain. An additional object provides for transforming the alkylidenedioxy compounds into substances containing an additional substituent at C21, and also to subsequently regenerate the dihydroxy side-chain leaving the additional substituent/ s at C-2l intact. Other objects will become evident from the detailed description set forth below.

I have found that when a steroid possessing the 17,21- dihydroxy-ZO-keto function is treated with a ketone, aldehyde, acetal or preferably a lower alkyl ketal, in the presence of a small amount of strong acid, there is formed the 17,2l-alkylidenedioxy group having the structure:

wherein R represents hydrogen, lower alkyl and aryl and=R represents lower alkyl, aryl or together with the 3 ,116,289 Patented Dec. 311, 1963 carbon atom to which they are attached, R and R form a 5-6 membered isocyclic ring.

My new process may be described as being applied to a steroid of the pregnaneseries having a dihydroxyacetone side chain at C-17 according to the following reaction:

wherein R represents hydrogen, lower alkyl and aryl and R represents lower alkyl, aryl or together with the carbon atom to which they are attached, R and R form a 5-6 membered isocyclic ring, and P represents oxygen or a bis-lower alkoxy group.

By steroids of the pregnane series I refer to all compounds possessing the perhydro cyclopentanophenanthrene ring to which is attached in the l7-position the dihydroxyacetone side chain. Additional substituents such as carbonyl functions at 3 or 11; lower alkyl such as methyl at one or more of positions 2,6,16; halogen at one or more of positions 2, 4, 6, 9, 11, 12; hydroxy at one or more of positions 1, 2, 3, 11, 12; unsaturation at 1, 4, 5, 6, 7, 9; and the like may be optionally present. In fact it is by virtue of the nature of this invention that such and other additional substitution may be introduced when not present without disturbing the labile dihydroxyacetone side chain at 0-17.

As the carbonyl reactant in my process, there may be employed aliphatic ketones such as acetone, methylethyl ketone, 3-pentanone and the like, cycloaliphatic ketones such as cyclohexanone, cyclopentanone and the like, aromatic ketones such as propiophenone, benzophenone and the like, aldehydes such as acetaldehyde, benzaldehyde and the like. I prefer to use the carbonyl reactant in the form of its lower alkyl acetal or ketal since I have obtained better yields and have been able to more easily separate and purify my product than when the free ketone or aldehyde of such reagents is used. Lower alkyl ketals of acetone, particularly 2,2-dirnethoxypropane, are the reagents of choice.

The reaction is preferably carried out in a non-reactive, non-aqueous solvent. I prefer a polar solvent such as dimethylformamide but other solvents may be employed such as tetrahydrofuran and dioxane. The acid catalyst is preferably a strong acid such as p-toluenesulfonic acid; however, other strong acids such as sulfuric, hydrochloric or trifiuoracetic may be employed. In actuality, any acid having a log K of less than 2.25 may be employed as catalyst.

The time required to effect optimum yield of the 17,21- alkylidenedioxy group will vary depending on the temperature of reaction and reactivity of the steroid. The reaction may be followed by employing stains which are specific for the dihydroxyacetone side chain such as blue tetrazolium. Normally present functional groups or sub- '3 stituents elsewhere in the fused ring portion of the pregnane molecule do not interfere with the formation of the 'alkylidenedioxy group.

In general, my invention covers novel compounds of the pregnane series possessing the following structure at the carbon atom designated as -17:

wherein R and R are as previously defined and Z is a member of the group consisting of H (H, lower alkyl), (H, lower alkanoyl), (H, aralkyl), alkylidene, aralkylilene, alkylene, lower alkyl and aryl substituted alkylene.

More specifically my novel compounds may be represented as having one of the following structural formula:

wherein R R and Z are as previously defined; A is a member of the group consisting of H and methyl; B is a member of the group consisting of H, methyl and halo gen; D is a member of the group consisting of H, lower alkyl and lower alkylidene; X is a member of the group consisting of hydrogen and halogen; Y is a member of the group consisting of O (H,OI-I) and (H,O-acyl); Q and T each represent halogen; and the 1,2-dihydro analogs of the foregoing.

Typical compounds embraced by the general structural formulae, III and IV, depicted above are the following pregnadienes, as well as their 1,2-dihydro analogs and their 21-(1,2-ethylene) analogs: 9a,1lfl-dichloro-l7a,21- isopropylidenedioxy 1,4-pregnadiene-3,20-dione, 90:,11B- dichloro-16(a and B)-methyl-17a,21-isopropylidenedioxy- 1,4-pregnadiene-3,ZO-dione, the 6u-methyl and the 64!- fiuoro analogs of the foregoing, 9a,11[i-dichl0ro-16-methylene 17a,2l isopropylidenedioxy-1,4-pregnadiene-3,20- dione, 90:,115 difluoro 1704,2l-isopropylidenedioxy-1,4- pregnadiene-3,20-dione, its 16-methyl analogs and the 604- methyl and 6a-fluoro analogs of the foregoing, the 90cfiuo'ro-l lfl-chloro analogs of the foregoing, the 90c-Chl01'0- llfi-fiuoro analogs of the foregoing, the 9oc-bfOInO-1lflchloro analogs of the foregoing, the 9ot-Chl010-17oc,2lisopropyl idenedioxy 1,4 pregnadiene-l l-B-ol-3,20-dione llfl-formate; 9u-chloro-16 (ea or ,8)-methyl-17u,21-isopropylidenedioxy-1,4-pregnadiene 11,6-ol-3,20-dione 11/3- formate; 9a chloro-17a,2l-isopropylidenedioxy-1,4-pregnadiene-l1fl-0l-3,20-dione llfl-acetate; 9a-bromo-17a,2lisopropylidenedioxy 1,4-pregnadiene 11;8-ol-3,20-dione 11 fi-propionate; a chloro-17a,2l-isopropylidenedioxy-l, 4-pregnadiene-l1,8-ol-3,20-dione llfi-diethylacetate; 9achloro 16 methylene 17a,21-isopropylidenedioxy-1,4- pregnadiene-l lB-ol-3,20-dione llfi-formate; as well as the 6a-methyl and 60c-fl11010 analogs of the foregoing. Although the isopropylidenedioxy group is preferred, there also may be employed Z-butylidenedioxy, 3-pentylidenedioxy, phenyl-Z-propylidenedioxy, as well as alicyclic groups such as cyclohexylidenedioxy, and the like.

Other representative examples of new pregnanes made by our process from the corresponding 17u,21-dihydroxy- 20-keto-pregnanes are l7pc,21isopropylidenedioxy-4-pregnene3,l1,20-trione; 1701,21 isopropylidenedioxy-4-pregnene-11/3-ol-3,20-dione; 1711,21 isopropyIidenedioxy-1,4- pregnadiene-3,11,20-trione; 1711,21 isopropylidenedioxy- 1,4-pregnadiene-11/3-ol-3,20-dione; the 9a-halogeno, especially the 9oc-flu0r0 analogs of the foregoing; 9a-fiuoro- 16cc methyl-:,21-isopropylidenedioxy-1,4-pregnadiene- 11fl-ol-3,20-dione; 6a-methyl-170:,2l-isopropylidenedioxy- 1,4-pregnadiene-1 1,8-01-3 ,ZO-dione; 9a-fiuoro-165-methyl- 17a,21 isopropylidenedioxy-l,4-pregnadiene-1 15-01-120- dione; 17oc,21 isopropylidenedioxy-4-pregnene-1la-o1-3, 20-dione; 17a,21 isopropylidenedioxyallopregnane-3,20- dione; 17a,21 isopropylidenedioxypregnane-3-ol-20-one; 1705,21-(phenyl-Z-propylidenedioxy) 1,4 pregnadiene-3, 11,20-trione; and the like, as well as the Z-butylidenedioxy, 3-pentylidenedioxy, phenyl-2-propylidenedioxy, as Well as alicyclic groups such cyclohexylidenedioxy, and the like of the foregoing.

The products are purified by extraction into an organic solvent followed by recrystallization from a suitable solvent or separation by known techniques such as chromatographic means.

Unlike other derivatives which have been employed for protection of the dihydroxyacetone side chain, such as the l7(20),20(21) bismethylenedioxy group, 20 semicarbazone, or the ZO-ethyleneketal, my novel 17,2l-alkyl idenedioxy group does not involve the C-20 carbonyl. Thus this carbonyl is free to enter into or activate subsequent transformations if so desired. With the ZO-keto group remaining intact, the activation of the C-21 carbon atom, apparently arising from this carbonyl group, is undisturbed. Thus in the presence of a strong base, various groups can be introduced at the 21-position. Such groups include the alkyl radicals from alkyl halides; acyl radicals from carboxylic acid esters; and alkylidene and aralkylidene groups arising from the condensation of an appropriate aldehyde or ketone followed by spontaneous dehydration. Further reaction can subsequently be accomplished once the above introduction has taken place.

Thus, for example, treatment of 17a,21-isopropylidenedioxy 1,4 pregnadiene 11,8-o-l-3,20-dione with methyl chloride, ethyl acetate, or formaldehyde in the presence of potassium t-hutoxide results in the formation of respectively, 17a,21 isopropylidenedioxy-Zl-methyl-1,4-pregnadiene-11B-ol-3,20-dione; 17a,21 isopropylidenedioxy-Zlacetyl-1,4-pregnadiene-11/i-ol-3,20-dione; and 17a,21-isopropylidenedioxy-21-methylene 1,4 pregnadiene-l Iii-ol- 3,20-dione. The reaction of 17a,2l-isopropylidenedioxy- 21-methylene-1,4-pregnadiene-1l,8-ol-3,20-dione with diazomethane will result in the formation of 17a,21-isopropylidene-2l-(1,2-ethylene) 1,4-pregnadiene-11fl-ol-3, ZO-dione. Subsequent cleavage of the 17u,21-isopropylidene side chain will produce the 21-(1,2-ethylene)-1,4- pregnadiene-l1,6,l7ct,21-triol. These reactions are general for the introduction of such groups at C-21.

Thus my novel process provides a method for preparing a new group of compounds of the pregnane series having further substituents C-2l. These new compounds are valuable in the treatment of inflammatory. diseases and have physiological effects similar to the C21 unsubsti tuted analogs.

The protective grouping described heretofore may also be utlized with modification in reactions wherein strongly basic conditions are required but where reaction at C-2l is to be avoided. For example, in the alkylation leading to the formation of Z-methylprednisolone, the dihydroxyacetone side chain is protected by formation of the 170;,21- alkylidenedioxy function as heretofore described. Subsequent formation of ZI-benzylidene-l7a,2l-alkylidenedioxy compound by treatment with benzaldehyde eliminates the possibility of any further alkylation. Hence with such two-fold protection even in such strongly basic media as potassium in liquid ammonia, alkylations may be executed Without fear of attack on the C-l7 side chain. The 21- benzylidene group specifically has the additional advantage of being cleaved simultaneously with the cleaving of the l7a,2l-alkylidenedioxy blocking group by refluxing in strong aqueous acid, with the result that the original dihydrox'yacetone side chain is regenerated.

As an alternative, the reactivity at C-2l may be lowered by' merely reducing the C- carbonyl group to hydroxyl. Strongly basic reactions may then be executed without fear of simultaneous reactions taking place at C-Zl. Later reactions at C2 1 are made possible by merely oxidizing the C-20 hydroxyl back to a carbonyl group. It is thus possible to selectively introduce the same or different groups at various positions in the steroid nucleus as for example preparing 2,21-dimethyl-cortisone or 60:- methyl-2l-acetylprednisone.

While the l7a,2l-alkylidenedioxy function can be cleaved by refluxing in aqueous acid such as 50% aqueous acetic acid or 50% formic acid, it is stable in the presence of small quantities of strong acid. Thus, for example, the l7zx,2l-isopropylidenedioxy group is not cleaved during the reaction of a 17a,2.ldihydroxy 3-ketopregnene and ethylene glycol to form the 3-ethylene ketal in the presence of small amounts of p-toluenesulfonic acid.

The 17a,2l-alkylidenedioxy function is also highly advantageous in protecting the side chain during the oxidation of various hydroxy groups in the nucleus. For example, in converting an 11 fi-hydroxy to an ll-keto group in a compound wherein the cortical side chain is present, simple esterification will protect a 21-hydroxy1, since the llB-hydroxyl is difficult to esterify and little danger exists of the 115,21-diester forming. In the case of the llahydroxy epimer however, esterification readily takes place at both the 11 and 2l-hydroxyl and hence selective means must be employed, as for example the use of only one equivalent of the esterifying agent. This complicating feature is obviated however with the use of l7a.,2l-alky1- idene function.

The 17a,2l-alkylidenedioxy function also serves as an effective blocking group for performing dehydrohalogenation reactions. Thus pregnane-ll;3,l7u,21-triol-3,20-dione is converted to the corresponding 17a,21-isopropylidenedioxy compound and then brominated under basic conditions as for example bromine and sodium acetate in acetic acid. The compound thus prepared, 2,4-dibromol7a,21-isopropylidenedioxypregnane-1lB-o1-3,20dione, is next treated with dimethylformamide yielding the corresponding 1,4-pregnadiene which when subjected to the action of refluxing 50% acetic acid is converted to prednisolone.

My novel blocking group is also well suited for executing certain oxidative conversions. Thus when subjecting the 17a,2l-isopropylidenedioxy derivative of 5(6)-pregnene-3/3,l7a,2l-triol-20one to the action of chromium trioxide in pyridine, there is formed 170t,2l-lSOPI'OPY1- idenedioxy-4-pregnene-3,20-dione which may be cleaved by the action of acetic acid to yield Reichsteins Compound S.

The l7u,2l-alkylidenedioxy function is particularly valuable in protecting the dihydroxyacetone side chain of a pregnane during an Oppenauer oxidation. For example, treatment of l7oc,21-isopropylidenedioxy-5pregnene- 3 6-o1-11,20-dione with aluminum isopropoxide in cyclohexanone results in the formation of l7a,2l-isopropylidenedioxy-4-pregnene-3,l1,20-trione, which upon cleavage in the prescribed manner yields cortisone.

The requisite starting materials of the compounds of Formula *III wherein Z represents H, are prepared according to the methods in the art including US. Patent No. 2,986,574. Those intermediates wherein Z represents some group other than hydrogen are prepared according to methods hereinafter exemplified. According to these procedures a 7u-2l-alkylidenedioxy compound may be substituted in the 2l-position by virtue of the C-20 keto group which apparently activates the carbon atom at the 21-position. By employing a 17a,21-alkylidenedioxy-3,20- diketo-l,4,9(l1)-pregnatriene or 4,9(1l)-pregnadiene in my process there may be introduced in the ZI-position an alkyl, alkylidene, aralkyl, aralkylidene, or an acyloxy group. These 21-substituted dienes and triene-s possessing the l7a,2l-alkylidenedioxy function are then readily converted to the corresponding :,21-di0l by cleavage of the alkylidenedioxy group with for example 50% formic acid. The 9u-halogeno-1l5-acyloxy function is then introduced by methods described in the art.

Those compounds of our invention wherein D in Formulae III and IV represents alkylidene are prepared from the corresponding l6-alkylidene-1,4,9(1l)-pregnatriene- 170a,21-di0l-3,20-dl0I16S and l6-alkylidene-4,9(1l)-pregnadiene-l7a,2l-diol-3,20-diones (in which the additional substitution at C-2 and C6 as shown in Formula IV may be optionally present). These 16-alkylidene compounds are prepared according to the methods described in US. application, Serial No. 861,211 filed December 22, 1959. This process in brief is as follows:

By treating 16-methyl-5,16-pregnadiene-3,li-ol-ZO-one with hydrogen peroxide there is prepared Rip-methyl- 16,17-oxido-5-pregnene3B-ol-20bne. This compound is then esterified so as to form for example the B-acetate and then treated with hydrogen bromide in acetic acid to cleave the 16,17-oxido ring. The product thus formed, 16 methylene 5 pregnene 3,8,17u-diol-20-one 3-acetate is next converted to the corresponding 3,2'l-diacetate through bromination at 21, conversion to the Zl-iodo compound and treatment with potassium acetate to yield 16 methylene 5 pregnene-3,8,17a,2l-triol-20-one 3,21- diacetate. Conversion of the 3-acetoxy-A -system to the 3-keto-A -system is then effected by the microbiological action of a culture of Flavobacterium dehydrogenans var. hydrolytz'cum and introduction of thellB-hydroxy group by the action of the microorganism Curvularia lunatcl. The compound obtained after these two successive microbiological transformations is l6-methylenehydrocortisone, which is readily converted to l6-methyleneprednisolone by subjecting it to the dehydrogenating action of the microorganism Bacillus sphaerz'cus.

Reacetylation of the 2l-hydroxy group of these two compounds followed by dehydration with p-toluenesulfonyl chloride then forms respectively 16-methylene- 4,9(11)-pregnadiene-17a,21-diol-3,20-dione 2l-acetate and 16 methylenel,4,9(11)-pregnatriene-l7a,2l-diol-3-20-dione ZI-acetate.

The foregoing method for the preparation of the aforementioned 16-methylene compounds and the compounds disclosed therein are specifically disclaimed herein.

Hydrolysis of the 16-methylene-4,9(ll)-pregnadiene- 17a,21-diol-3,20-dione 21-acetate and corresponding 1,4,9(ll)-pregnatrienes may then be effected by known methods to obtain the corresponding free 21-hydroxyl compounds. Introduction of the 9u-halogeno, llfl-acyloxy and 17a,2l-alky1idenedioxy functions are then exeouted as described above. Similarly the various 21-substituents described herein may be introduced according to the methods also recited herein. These reactions may be summarized as follows wherein the 16-alkylidene group is exemplified below by methylene and wherein the substituents A, B and Z are as described heretofore CH CH3 (111120000113 CHZOH C C=O These 16-methy1ene-4,9(11)-pregnadienes and 16- methylene-1,4,9(11)-pregnatrienes are the precursors for novel compounds included within the scope of my inven tion. By subjecting for example 16-methylene-l,4,9(11)- pregnatriene-17u,21-diol-3,20-dione Zl-acetate to the 9,11- di-halogenation procedures described herein, for example, the dichlorination process, the'e is obtained 90,l1fldichloro-16-methylenc-1,4-pregnadiene 17a,2l-di0l-3,20- dione ZI-acetate. Saponification of this compound yields the corresponding free 2l-alcohol which when treated with 2,2-dimethoxypropane in the presence of acid catalyst yields 9a,1lfi-dichloro-l6-rnethylene-17a,21-isopr0- pylidenedioXy-l ,4-pregnadiene-3 ,ZO-dione.

The requisite steroid starting materials for the compounds of Formula IV and shown in the foregoing reaction are prepared as described in US, Patent No. 2,894,963.

The novel 9a,11,B-dihalo compounds also form a basis for preparing higher homologs and derivatives attached to C-21. The 17-,21-alkylidenedioxy function permits further reaction such as additional substitution at C-Zl to take place without destruction of the side chain. In View of its adjacency to the 20-keto group, the C21 carbon atom may be further reacted under appropriate conditions which maintain the alkylidenedioxy group intact. For example, reaction of 9a, l1(3-dichloro-17o,2l-isopropylidenedioXy-l,4-pregnadiene-3,20-dione with formaldehyde in the presence of sodium bicarbonate results --on Ton,

in the formation of 9:,11,8-dichloro-17,2l-isopropylidenedioxy-Z1-methylene-1,4-pregnadiene-3,ZO-dione. The 21- methylene group may be reduced to methyl by means known to selectively reduce such a conjugated double bond without affecting the keto groups present. Alternatively, the l7u,2l-alkylidenedioxy compound may be alkylated with a methyl halide to give rise to a ZI-methyl- 17,21-alkylidenedioxy compound. Similarly, the 21-position of our novel compounds may be acylated with an appropriate agent to produce the Zl-acyl product. For example ,11fl dichloro 16o: methyl-17,21-isopropylidenedenedioxy-l,4-pregnadiene-3,20-dione upon reaction with ethyl acetate in the presence of base gives rise to 90,1lp-dichloro-l7tt,2l-isopropylidenedioxy 21 acetyl- 1,4-pregnadiene-3,ZO-dione, i.e., 21-substituted compounds are themselves therapeutically active in the same areas of medication for which the ZI-unsubstituted compounds are useful. In each instance, the alkylidenedioxy group may be cleaved by means of acid or base giving rise to the original starting steroid which now possesses a further substituent at C21.

It is apparent from the foregoing that a wide variety of reactions may be carried out upon pregnanes whose dihydroxy-acetone side chains are protected by my novel l7ot,2l-alkylidenedioxy function. These reactions include epoxide ring openings, saponifications, brominations, dehydrohalogenations, alkylations, oxidations, reductions, ring closures, and the like. In addition, merely by refluxing the reaction product in aqueous formic or aqueous 9 acetic acid, there is regenerated the undisturbed dihydroxy-acetone side chain.

In addition to its value as a protective group for executing synthetic or degradative reactions elsewhere in the steroid molecule as described above, the presence of the 17,2l-alkylidenedioxy function also enhances the effectiveness of various steroids which exhibit therapeutic activity. Thus the 17,2l-isopropylidenedioxy derivative of 9a-fluoro 16a methyl 1,4-pregnadiene-1lfi,l7a,21-triol- 3,20-dione shows prolonged and enhanced anti-inflammatory activity and is particularly valuable in topical therapy of inflammatory conditions. The new 9,1l-dihalogeno compounds and the 9a-halogeno-11B-acyloxy pregnenes of my invention falling within the general Formulae III and IV are strong anti-inflammatory agents which advantageously are not salt retaining. In particular, 904,113- dichloro-lfia methyl 17,21 isopropylidenedioxy-1,4- pregnadiene-3,20-dione is about 10-12 times more potent than its corresponding 17,21-dihydroxy compound when tested as an anti-inflammatory agent in the well-known granuloma pouch test, and the 9a-chloro-16a-methyl- 17ml1isopropylidenedioxy-l,4-pregnadiene-11p 01-3 ,20- dione llB-formate is about 16 times more potent than prednisolone when tested as an anti-infiammatory agent in the granuloma pouch test. Also, the 17,21-isopropylidenedioxy derivative of 9ot-fluoro-16a-methyl-1,4-preg nadiene-l1fi,17e,2l-triol-3,ZO-dione shows prolonged and enhanced anti-inflammatory activity and is particularly valuable in topical therapy of inflammatory conditions.

In essence, where the 17a,21-dihydroxy-20-keto steroid is physiologically active and therapeutically useful, its corresponding l7a,2l-alkylidenedioxy analog is also valuable. As indicated above, the cyclic grouping enhances effect, provides for longer duration of action and it is particularly useful in topical therapy. My novel therapeutically valuable compounds may be administered in pharmaceutical dosage forms such as creams, ungents, tablets, elixirs and the like. Topical preparations advantageously contain from about 0.1 to about 0.5% of alkylidenedioxy compound. Such preparations are valuable in the alleviation of burns and the treatment of certain atopic and contact dermatoses.

These valuable pregnenes are also useful in the veterinary field, particularly in the treatment of small animals exhibiting inflammatory disorders. In view of their greatly enhanced activity, smaller doses than are usually employed with anti-inflammatory steroids may be used advantageously with the result that hormonal side effects are minimized.

While the aforementioned thereapeutic uses are also true of the 4-pregnene of our invention, the 1,4-pregnadienes are by far the more potent. However, the 4- pregnenes While being less potent still have the advantage of being useful as intermediates. For example, upon microbiological dehydrogenation with an organism such as Corynebacterium simplex according to known procedures, the 4-pregnenes may be transformed into the more potent 1,4-pregnadienes.

The following examples will serve to typify several preparative routes suitable for our novel compounds. These examples however should not be construed as limiting the scope of this invention, the scope of which is limited only by the appended claims.

EXAMPLE 1 1704,21 -Ispr0pylidenedioxy-I,4-Pregnadiene-1 1,8-01- 3,20-Di0ne A solution of 2.0 g. of prednisoline in 4 cc. of dimethylformamide and 15 cc. of 2,2-dimethyoxypropane to which has been added a crystal of p-toluenesulfonic acid is refluxed for 6 hrs. The solvents are then removed in vacuo and the residue dissolved in benzene and absorbed on 40 g. of acid-washed alumina. Elution with benzene and chloroform-benzene 1:2 and crystallization from acetone yield 17u,2l-isopropylidenedioxy-1,4-pregnadiene- 1t) 11,B-ol-3,20-dione, M.P. 243-247 0., [a] (chloroform).

EXAMPLE 2 1 711,21 -Is0pr0pylidenedi0xy-2l -Methyl-1 ,4-Pregnad i enel 1l3-Ol-3,20-Di0ne A solution of potassium t-butoxide is prepared from 700 mg. of potassium in 50 cc. of t-butanol and to it is added 1.0 g. of 17ot,2l-isopropylidenedioxy-l,4-pregnadiene-llfi-ol-3,20-dione. After solution has occurred, 15 cc. of methyliodide are added and the mixture is refluxed under a nitrogen atmosphere with stirring for 2 hours. The mixture is poured into water and extracted with chloroform. The chloroform solution is next dried over sodium sulfate and concentrated in vacuo. The residue is then crystallized twice from acetone to yield 17cc,21-lSO propyl-idenedioxy 21 methyl-1,4-pregnadiene-1Idol- 3.20-dione, M.P. 245 [a] +93 (chloroform).

EXAMPLE 3 21 -Methylprednisolo ne A solution of 612 mg. of 17a,2l-isopropylidenedioxy- 2l-methyl-1,4-pregnadiene,11B-ol-3,20-dione in 10 cc. of acetic acid and 10 cc. of water is heated on a steam bath under a nitrogen atmosphere for 1.5 hours. The solution is then concentrated in vacuo and the residue crystallized from acetic acid and ether and recrystallized from acetic acid to yield 21-methyl-prednisol0ne, M.P. 129-133, [u] =l-5 6 (chloroform).

EXAMPLE 4 21 -Methylprednis0l0ne 21-Acetate A solution of 100 mg. of ZI-methylprednisolone in 1 cc. of pyridine and 1 cc. of acetic anhydride is allowed to stand overnight. The solvents are then removed in vacuo and the residue crystallized twice from acetonehexane to yield 21-rnethylprednisolone 21-acetate, M.P. 218224, [a] +97 (chloroform).

EXAMPLE 5 21 -M ethylene-1 7a,2l -Is0pr0pylidenedi0xy- 1,4-Pregnadiene-1l/3-Ol-3,20-Di0ne To a solution of 3.0 g. of 17u,2l-isopropylidenedioxy- 1,4-pregnadiene-11fl-ol-3,20-dione in cc. of ethanol is added 750 mg. of sodium bicarbonate and 30 cc. of 37% formaldehyde solution. The mixture is stirred at 6570 for 16 hours and water is then added. The ethanol is next removed in vacuo. The residue is filtered, washed with water, and recrystallized from acetone to yield 21-methylene-17u,2l-isopropylidenedioxy-1,4-pre nadiene-l1fi-ol-3,20-dione, M.P. 2132l5, [a] +286 (chloroform) EXAMPLE 6 9wFIu0r0-16u,21-Dimethyl-1 711,21 -Is0pr0pylidenedi0xy- 1,4-Pregnadiene-J1B-Ol-3,20-Di0ne To a solution of 290 mg. of potassium of 100 cc. of dry t-butanol are added 802 mg. of 9u-fluoro-16a-methyl- 170:,21 isopropylidenedioxy-1,4-pregnadiene-1Idol-3,20- dione. After the steroid is completely dissolved at room temperature, 20 cc. of methyliodide are added and the mixture is stirred at room temperature for 15 minutes under a nitrogen atmosphere. The solution is then poured into water and the mixture extracted with chloroform. The chloroform extracts are dried over sodium sulfate and concentrated to dryness in vacuo. The residue is crystallized from methylene chloride-ether and recrystallized from acetone to yield 9tx-fiuoro-16a,21-dimethyl- 170;,21 isopropylidenedioxy-1,4-pregnadiene-115-01-320- dione, M.P. 252258, [a] +72 (chloroform).

EXAMPLE 8 9oc-Flu0l'0-160,21-Dimethylprednis0l0ne A solution of 90' mg. of 9a-fluoro-16a,21-dimethyl-17a, 21-isopropylidenedioxy 1,4 pregnadiene-11fl-ol-3,20- dione in 7 cc. of 50% formic acid is heated for 2 hours on the steam bath under a nitrogen atmosphere. Water is next added and the solution concentrated to dryness in vacuo. The residue is crystallized twice from methylene chloride, and dried in high vacuum at 140 to yield 90cfluoro 1611,21 dimethylprednisolone, M.P. 243-246, [a] +79 (chloroform).

EXAMPLE 9 9oc-Flu0r0-16a,21-Dimethylprednisolone 21 -A cetate A solution of 350 mg. of 9ot-fluoro-16a,21-dimethylprednisolone in 2 cc. of pyridine and 2 cc. of acetic anhydride is allowed to stand overnight. The solvents are then removed in vacuo and the residue crystallized from methanol to yield 9a-fiuoro-l6ix,2l-dimethylprednisolone ZI-acetate, 150 mg, M.P. 234240.

EXAMPLE 10 To a solution of 250 mg. of 90t-flllOI'O-160L-m6thyl-17OL, 21-isopropylidenedioxy 1,4 pregnadiene-11fi-ol-3,20- dione in 15 cc. of ethanol and 4 cc. of 37% formaldehyde solution is added 80 mg. of sodium bicarbonate. The mixture is stirred overnight at a bath temperature of 70. Water is then added and the ethanol removed in vacuo. The residue is filtered, dried and crystallized from acetone, to yield 9a-fiuoro-16a-methyl-21-methylene- 1701,21 isopropylidenedioxy-1,4-pregnadiene-11,8-ol-3,20- dione, M.P. 228-235, [a] +244 (chloroform).

EXAMPLE 11 71 u,21 Jsopropylz'denedioxy-Z] -Benzylidene- 1 ,4-Pregna diene-1 1 [3-01-32 O-Dione To a boiling solution of 2 g. of 17u,2l-isopropylidenedioxy-lApregnadiene-l1,6-ol-3,20-dione in 100 cc. of methanol is added 1 g. of sodium methoxide and 5 cc. of benzaldehyde. The solution is stirred overnight at 50 during which time the gradual precipitation of the benzylidene derivative occurs. To the cooled mixture is added 125 cc. of water and the solid formed collected by filtration. After drying, the material is crystallized from acetone-methanol to yield 17a,21-isopropylidenedioxy-21-benzylidene-1,4-pregnadiene-11/8-ol-3,20 dione, M.P. 289292.

EXAMPLE 12 1 711,21Jsopropylidenedioxy-12-Nitr0methyl-1,4- Pregnadiene-I1,8-Ol-3,20-Di0ne To a solution of 50 mg. of sodium in cc. of methanol is added 412 mg. of 17ot,2l-isopropylidenedioxy-1,4-pregnadiene-l1,6-ol-3,20-dione. After heating to bring the steroid into solution, 0.1 cc. of nitromethane in 0.15 cc. of methanol is added dropwise. The solution is refluxed for 15 minutes, cooled and acidified with dilute acetic 12 acid. Further dilution with water precipitates a solid which is collected by filtration and dried. The solid is next dissolved in benzene and adsorbed in 6 g. of Florisil. The benzene-ether, 1:1, fractions affords 17a,21-isopropylidenedioxy 21 nitromethyl-1,4-pregnadiene-1lfl-ol- 3,20-dione which is recrystallized from ether, M.P. 225- 228.

EXAMPLE 13 1 701,21-Isopr0pylidenedioxy-l,4-Pregnadiene-3-Onc- 11,8,20B-Diol To a solution of 400 mg. of 17u,21-isopropylidenedioxy-1,4-pregnadiene-11,8-ol-3;20-dione in '40 cc. of dimethylformamide is added a solution of mg. of sodium borohydride in 5 ice. of water. The solution is allowed to stand overnight at room temperature, cooled and the excess sodium borohydride decomposed by addition of acetic acid. The solution is next diluted with Water and the precipitated solid filtered, dried, and crystallized from acetone to yield 17a,2l-isopropylidenedioxy-1,4-pregnadiene-3-one-115,20flsdi0l, M.P. 233237, [OC]D+67 (ohloroform) EXAMPLE 14 1 70,2]-(2-Butylidenedioxy)-1,4-Pregnadiene-11fl- 0l-3,20-Di0ne By substituting 2, 2-dimethoxybutane for 2,2-dimethoxypropane in the procedure of Example 1 there is prepared upon purification as therein described, 17ct,21-(2- butylidenedioxy)-1,4-pregnadiene-1-1,B-ol-3,20-dione.

In a similar fashion by substituting 2,2-dimethoxypentane, 1,I-dimethoxycyclohexane, 3,3-dimethoxypentane, and the like for 2,2-dimethoxypropane in the procedure of Example 1, there are prepared respectively 17ix,21-(2- pentylidenedioxy) 1,4 pregnadiene 11,8 ol 3,20- dione, :,21-cyclohexylidenedioxy-1,4-pregnadiene-11/3- ol-3 -20- dione, 1704,21- (3-pentylidenedioxy) -1,4-pregr1adiene-11/3-ol-3,20-dione, and the like.

Likewise, various other dialkyl groups may be substituted for methyl in the starting material. Hence, 2,2-diethoxypropane or idipropoxypropane may be employed in place of dimethoxypropane in the first example.

EXAMPLE 15 1,4-Pregnadiene-170,2Z-Di0l-3,11,20-Tri0ne A. Two grams of allopregnane-l7u,21-diol-3,11,20- trione are treated with 2,2-dimethoxyprop-ane in the manner of Example 1. There is thus prepared upon purification in the prescribed manner, the compound 17a,21-isopropylidenedioxyallopregnane 17a,21 diol 3,11,20- trione.

1B. To one gram of 17tt,21 isopropyliidenedioxyallopregnane-17u,21-diol-3,11,20-trione in 10 cc. of acetic acid is added 0.8 g. of sodium acetate. The mixture is then treated with 0.8 g. of bromine and stirred for 4 hours. Water is next added to precipitate the crude product which is collected by filtration and refluxed without further purification in 50 cc. of dimethyl formamide for one hour. Chloroform and water are next added and the organic layer is separated and washed with water. The organic extracts are then reduced to a residue consisting essentially of 17,2l-isopropylidenedioxy-1,4-pregnadiene-3,11,20-trione which is employed in the next step without purification.

C. The crude material prepared in part B of this example is treated with 10 cc. of acetic acid and 10 cc. of water in the manner of Example 3. There is thus prepared upon purification as therein described, the compound of this example 1,4-pregnadiene-17a,21-diol-3,11, 20-trione.

EXAMPLE 16 4 Pregnene-1 7a,21 -D1'0l-3,1 1 ,ZO-Trione A. Ten grams of 5-pregnene-313,17oc,21-triol-11,20-dione are treated with 2,2-dimcthoxypropane according to the procedure of Example 1 with the quantities therein employed being increased five fold. Upon purification as therein described there is obtained 17u,21-isopropylidenedioxy--pregnene-3fi-ol-11,20-dione.

B. A mixture of 5 g. of 17u,21-isopropylidenedioxy-5- pregnene-3fi-ol-11,20-dione in 20' cc. of toluene and 500 cc. of cyclohexanone containing 2 g. of aluminum isopropoxide is refluxed for 2 hours. At the end of this time the mixture is steam distilled to remove the organic solvents and the residue is then filtered. The solid thus obtained is triturated three times with methylene chloride and the organic extracts are then combined, dried, and evaporated to a solid. The solid is then crystallized from acetonehexane to yield 17a,21-isopropylidenedioxy-4-pregnene- 3,11,2G-trione.

C. The compound prepared in part B of this example is heated in cc. of formic acid and 10 cc. of water on a steam bath under a nitrogen atmosphere for 1 /2 hours. The solution is then concentrated in vacuo and the residue crystallized from acetic acid and ether and recrystallized from acetic acid to yield 4-pregnene-17a,21-diol3,11,20- trione.

Alternatively the compound of this example may be prepared according to the following procedure wherein the 17u,21-all ;ylidenedioxy function is also advantageously employed. 1

Following the procedure of Example 1 with 4-pregnene-l1a,17a,21-triol-3,20-dione being substituted for prednisolone and increasing the quantities therein employed 5 fold, there is prepared 17a,21-isopropylidenedioxy-4-pregnene-11a-ol-3,20-dione. This compound is dissolved in cc. of pyridine and treated with a complex consisting of 2 g. of chromium trioxide and 20 cc. of pyridine. The reaction mixture is stirred for 18 hours at room temperature after which time 6 g. of sodium sulfite are added, care being taken to maintain the temperature below 30 C. The mixture is then extracted with methylene chloride and the organic extracts washed with water, dried, and evaporated to a residue. Crystallization of this residue from acetone hexane yields l7a,21-isopro pylidenedioxy-4-pregnene-3,1 1,20-trione.

This product, 17,21-isopropylidenedioxy-4-pregnene- 3,11,20-trione, is next treated with acetic acid and water in the manner of Example 3 and there is thus obtained upon purification as therein described, 4-pregnene-17a,21- diol-3,11,20-trione.

EXAMPLE 17 2-Methyl4-Pregnene-115,1 7u,21-Tri0l-3,20-Di0ne A. Hydrocortisone is substituted for prednisolone in the procedure of Example 1 with the quantities increased 5' fold and there is thus obtained upon purification in the prescribed manner, -17m,21-isopropylidenedioxy-4-pregnene-l 1B-ol-3,20-dione.

B. To a solution of 4.4 g. of 17a,21-isopropylidenedioxy-4-pregnene115-ol-3,20-dione and 3 cc. of diethyl oxalate in 50 cc. of t-butanol is added 1 g. of sodium methoxide While maintaining the temperature at 50 C. After /2 hour the mixture is cooled and the precipitated solid collected by filtration. This solid is then dissolved in water and then reprecipitated by the careful addition of dilute hydrochloric acid, care being taken to keep the pH above 7. The resulting solid, 2ethoxyoxaly1-l7ot,21- isopropylidenedioxy-4-ene-11,8-ol-3,20dione is dissolved in 20 cc. of acetone containing 15 cc. of methyl iodide and g. of anhydrous potassium carbonate and the mixture is stirred for 72 hours. Water is then added and the mixture is next extracted with methylene chloride. The organic extracts are then evaporated to an oily residue consisting essentially of Z-methyl-Z-ethoxyoxalyl- 170:,21 isopropylidenedioxy 4 pregnene 11B ol- 3,20-dione which is next dissolved in 25 cc. of methanol to which has been added 0.5 g. of sodium methoxide. This mixture is allowed to stand for 4 hours at room tem- 14 perature after which time the careful addition of water crystallizes the precipitate of 2-methyl-17ot,2l-isopropylidenedioxy-4-pregnene-11B-ol-3,20-dione. This material is then collected by filtration and treated with acetic acid and water in the manner of Example 3 to yield Z-methyl- 4-pregnene-1 1/3, 1711,21 -triol-3 ,20-dione.

EXAMPLE 18 1 70;,21 Jsopropy lidenedioxy -1 ,4,9 (1 1 -Pregnatriene- 3 ,ZO-D i one Two grams of 1,4,9(11)-pregnatriene-17a,21-diol-3,20 dione are treated with 2,2-dimethoxypropane in the manher of Example 1. There is thus prepared upon purification in the manner therein prescribed, the compound of this example, ;,2l-isopropylidenedioxy-1,4,9( 11)-pregnatriene-3,20-dione.

EXAMPLE 19 1711,21 -(1-Phenyl-Z-Propylidenedioxy -1,4-

Pregnadiene-3,1 1 ,2 O-Trione One gram of 1,4-pregnadiene-17a,21'diol-3,l1,20-tri one is dissolved in 15 cc. of benzene and to the solution is added 5 g. of l-phenyl-Z-propanone. A small quantity of anhydrous hydrogen chloride (about 1%) is then introduced and the mixture refluxed employing a Dean- Stark reflux apparatus for the removal of the water which is formed. The mixture is thus heated until water is no longer formed. The solution is then cooled and poured into water and extracted with methylene chloride. The methylene chloride extracts are next washed with water, dried, and evaporated to a residue and the residue chromatographed in the manner described in Example 1. There is thus prepared, 17a,2 1-(l-phenyl-Z-propylidenedioxy)-1,4-pregnadiene-3,11,20-trione.

EXAMPLE 2O 6a-Il/IGihyl-I 7 x,21Jsopropylidenedioxy-2I-Acetyl- 1 ,4 -Preg;mcli cue-3 ,1 1 ,2 O-Tri one A. Ga-WIETHYL-I'YaflLISOPROPYLIDENEDIOXY-1,4-

PRE GNADIENE3,11,20TRIONE Ten grams of 6a-methyl-1,4-pregnadiene-1'i'u,21-dio- 3,11,20-trio-ne are treated in the manner of Example 1 with the quantities therein described increased five fold. Upon purification in the prescribed manner there is obtained oat-methyl 17a,21 isopropylidenedioxy-1,4-pregnadiene-3,11,20-trione.

B. Ge-METHYL H ZLISOPROPYLIDENEDIOXYh1- ACETYL-l,4PREGNADIENE-3,l1,20-TRIONE Three grams of Gar-methyl-17ot,21-isopropylidenedioxy- 1,4-pregnadiene-3,1l,20-trione are added to 15 ml. of ethyl acetate and to the mixture is added a solution prepared from 20 ml. of t-butanol and 280 mg. of potassium metal. The mixture is then heated at reflux. temperature with provision made for the removal of the ethanol which is formed. The mixture is thusly heated for three hours, then cooled and poured into water. The water mixture is next extracted with chloroform, dried over sodium sulfate and reduced to a residue. Upon. recrystallization of the residue from acetone there is obtained 60- imethyl-17a,21-isopropylidenedioxy-2l-acetyl 1,4 pregnadiene-3,11,20-trione.

In a similar fashion by substituting 6a-fiuoro-1,4-pregnadiene-l7ot,21-diol-3,11,20-trione in the procedure of Example 20A, there is prepared 6a-fiuoro-17u,21-isopropylidenedioxy-1,4-pregnadiene-3,11,20 trione, which when treated in the manner of Example 208 is converted to oa-fiuoro 17a,21 isopropylidenedioxy-21-acetyl-1,4- pregnadiene-3,11,20-trione.

Likewise the esters of various other organic acids may be substituted for ethyl acetate in Example 208 and there may thus be prepared such compounds as 17a,21-isopropylidenedioxy-Zl-benzoyl-l,4-pregnadiene 11,8 ol- 3,20-dione, 9a-fluoro 17a,21 isopropylidenedioxy-21- EXAMPLE 21 9:1,115-Di0hl01'0-1 711,21{sopropyliden-edi xy-Z,4-

Pregnadiene-j,ZO-Dione A solution of 2.0 g. of 901,11,8-dichloro-1,4-pregnadiene-17a,21-diol-3,2G-dione in 4 ml. of dirnethylforl amide and 15 ml. of 2,2-dimethoxypropane to which has been added a crystal of p-toluenesulfonic acid is heated at reflux temperature for hrs. The reaction mixture is then concentrated in vacuo and the residue dissolved in benzene. This solution is then placed upon a chromatographic column and eluted with benzene and then with a 2:1 benzene in chloroform solution. The material which is first eluted is recrystallized from acetone to yield the compound of this example 9a,11,8-dichloro- 17a,21 isopropylidenedioxy-1,4-pregnadien -3,20-dione,

M.P. 212214 [a] 5,'-162 (dioxane).

In a similar manner the following 9a,11,8-dihalogeno pregnanes are subjected to the above reaction procedure:

9a-bromo-1LB-fluoro-l,4-prcgnadiene-17a-21-diol- 3,20-dione,

9oc-Chl0fO-1 1/3-l'luoro-1,4 pregnadiene-17a,2l-diol- 3,20-dione,

911,1lfi-difiuoro-1,4-pregnadiene-17a,21diol-3,20-dione,

9a-fluoro-1 1/3-chloro-4-pregnene-17a,21-diol-3,20-

dione,

9a-bromo-11fi-fluoro-4-pregnene-17a,21-cliol-3,2 0-

dione,

9tx-i0do-11fi-tluoro-1,4-pregnadiene-17u,21-diol-3,20-

dione,

90,l 1p-dichloro-4-pregnene-170.,21-diol-3,20-dione.

There is thus prepared respectively the following compounds:

9abro'mo-1 IB-fiuoro-17a,2l-isopropylidenedioxy-1,4-

pregnadiene-3 ,20-di0ne,

9a-chloro-l 1fi-fiuoro-17a,2 1-isopropylidenedioxy-1,4-

pregnadiene-3 ,ZO-dione,

90,1 lfl-difiuoro-17u,2l-isopropylidenedioxy-1,4-pregnadiene-3,20-dione,

9a-fiuoro-11,B-chloro-17,2l-isopropylidenedioxyipregnene-3 ,20-dione,

9a-bromo-11B-fluoro-17a,21-isopropylidenedioxy-4- pregnene-17ct,21-diol-3,20-dione,

9a-iOdO-1 lfi-fluoro-17a,21-isopropylidenedioxy-1 ,4-

pregnadiene-3 ,20-dione,

901,11,6dichloro-17a,21-isopropylidenedioxyl-pregnene-3,20-dione.

EXAMPLE 22 To a solution of 2 g. of 2-rnethyl-9a-chloro-1lfi fiuoro- 4-pregnene-17e,21-diol-3,20-dione in 4 cc. of dimethylforrnamide is added cc. of 3,3-dimethoxy pentane and a crystal of p-toluenesulfonic acid. The matter is refluxed for 6 hrs. and purified according to the procedure described in Example 21. There is thus obtained the compound of this example, 2-methyl-9a-chloro-ll,8- fluoro-l7a,21-(3-pentylidenedioxy) 4 pregnene 3,20- dione.

Use of 2,2-dimethoxy propane in the above procedure in place of 3,3-dimethoxy pentane results in the formation of 2 -methyl-9ct-chloro-11fi-flu0ro-17o,2l-isopropylidenedioxy-4-pregnene-3,20-dione.

9a,1IB-dichloro-lM-methyl 1,4 pregnadiene-17a,21- diol-3,20-dione is subjected to the reaction as described in Exampie 21 with the exception that the reflux period is extended to 15 hrs. Upon purification as therein described there is obtained the compound of this example ,1lfl-dichloro-ids-methyl 170.,21 isopropylidenedioxy-1,4-pregnadiene-3,20-clione, MP. 239 235 (dioxane).

In a similar fashion, by employing the l6fl-methyl epirner, 9a.,1lfi-dichloro-Ion-methyl 1,4 pregnadiene- 17a,21-diol-3,20-dione in the above procedure there is formed 9m,11fl-dicnloro 16,8 methyl 17a,21-isopropyl idenedioxy-1,4-pregnadiene 3,20 dione, MP. 20/212 [ac] -l159 (dioxane).

Likewise by substituting 9a-bron1o-1lfl-chloro-16aethyl-1,4-pregnadiene-17a,21-cliol-3,20-dione therein, the compound prepared is 9m-hromo-llfi-chloro-ltSa-ethyl- 17a,21-isopropylidenedioxy-1,4-pregnadiene-3,20-dione.

EXAMPLE 24 6a,9a,llfi-trifiuoro-1,4-pregnadiene 1704,21 dial-3,20- dione is refluxed for 12 hrs. with 2,2-dirnethoxypropane and p-toluenesulfonic acid according to the procedure of Example 21. There is thus obtained upon purification in the prescribed manner the compound, 60:,9a,11/3-t1ifl1l0f0- 17a,2l-isopropylidenedioxy-1,4-pregnadiene-3,20-dione.

in the same manner but with the reflux period extended to 15 hrs. 6m-fluoro-9a,1lfl-dichloro-lw-methyl- 1,4-pregnadiene-17a,21-diol-3,20-dione is treated with the above described reagents and there is prepared 60.- fiLlOI'0-9a,ll/3-diChlO1'O-l6,8m$thyl l7a,21 isopropylidenedioxy-1,4-pregnadiene-3,20-dione.

EXAMPLE 25 6a-Metlry l-9oc,]I/B-Dic/zloro-J 70,21Jsopropylidenedioxy- 1,4-Pregnadiene-3,20-Di0ne Two grams of 6ot-methyl-9m,1lfl-dichloro-1,4-pregna diene-17a,21-diol-3,29-dione are dissolved in 4 cc. of dimethyl-formamide and 15 cc. of 2,2-diniethoxypropane and a crystal of p-toluene-sulfonic acid is added. The reaction mixture is refluxed for 6 hrs. The solvents are then removed in vacuo, the residue dissolved in benzene and adsorped on 40 g. of acid Washed alumina and the column eluted with benzene and chlorofonm-henzene 2:1. Recrystallization from acetone of the material so obtained yields 6a-methyl-9a,11fi-dichloro-17a,2l-isopropylidenedioxy-l,4-pregnadiene-3,20-dione.

In a similar fashion by subjecting 6a-fluoro-9a,11fidichloro-1,4-pregnadiene-17a,21-diol-3,20-dione to the reaction procedure herein set forth, there is prepared the compound, 6a-fluoro-9a,11 3-dichloro-17a,2l-isopropylidenedioxy-1,4-pregnadiene-3,20-dione.

EXAMPLE 26 Qa-Ch'lom-J lfi-Fluoro-I 7o ,21Jsopropylidenedioxy- 21 -Methyl-1 ,4 -Pregnadiene-3 ,2 0-D one To 50 cc. of t-butanol are added 700 mg. of potassium metal and to the resultant solution of potassium t-butoxide are added 10 g. of 9a-chloro-1lfi-iluoro-lhil isopropylidenedioxy-l,4-pregnadiene-3,ZO-dione. There are next introduced 15 cc. of methyl iodide and the reaction mixture is then stirred at reflux temperatures under an atmosphere of nitrogen for two hours. The mixture is next poured into Water and extracted with chloroform. These extracts are concentrated to a residue in vacuo after being dried over sodium sulfate. Upon recrystall zation of the residue from acetone there is obtained, 9e-chloro-11fifiuoro 1711,21 isopropylidenedioxy 21 methyl 1,4- pregn'adiene-3,20-dione.

By substituting 9a,11B-dichloro-17a,2l-isopr-opyidenedioxy 1,4 pregnadiene 3,20 dione, 901,115 dichloro- 16a methyl 17ot,21 isopropylidenedioxy 1,4 pregnadiene 3,20 dione, 911,115 diiluo-ro 1704,21 isopropylidene/dioxy-1,4-pregnadiene-3,ZO-dione and the like in the above procedure, there are prepared respectively, 911,115 dichloro 1701,21 isopropylidenedioxy 21- rnethyl 1,4 pregnadiene 3,20 dione, 901,115 dichloro 1601,21 dimethyl 171x,21 isopropylidenedioxy- 1,4 pregnadiene 3,20 dione, 011,115 difluoro 171x, 21 isopropyllidenedioxy 21 methyl 1,4 pregnadiene- 3,20-dione and the like.

In a similar fashion by employing ethyl iodides, propyl iodide and the like in place of methyl iodide in the above reaction procedure, there are prepared respectively 90- chloro 11/3 fiuoro 1701,21 isopropylidenedioxy 21- ethyl 1,4 pregnadiene 3,20 dione and 911 chlorollfi fluoro 1701,21 isopropylidenedioxy 21 propyl- 1,4-p-regnadiene-3,20-dione.

EXAMPLE 27 9a,11,3DiClll0r0-1 701,21 Jsopropylidenedioxy-Zl M ethylene-1 ,4-Pregnadierze-3,20-Dione Three grams of 911,1lfl-dichloro-170:,21-isopropylideno dioxy-1,4-pregnadiene-3,20-dicne are dissolved in 120 cc. of ethanol and to the resultant solution is added 750 mg. of sodium bicarbonate and 30 cc. of 37% formaldehyde solution. The reaction mixture is then stirred at 65 70 C. for 16 hours, after which time water is added and the ethanol removed in vacuo. The solid which forms is collected by filtration, washed with water, and recrystallized from acetone to yield 901,11/3-dichloro-171x,2l-isopropylidenedioxy 21 methylene 1,4 pregnadiene- 3,20-dione.

In a similar fashion by substituting 901,11B-dichlor- 161x methyl 1701,21 isopropylidenedioxy 1,4 pregnadiene 3,20 dione; 901,116 dichloro 16,8 methyl- 1701,21 isopropylidenedioxy 1,4 pregnadiene 3,20- dione; and 61x methyl 901,115 dichloro 1701,21 isopropylidendioxy 1,4 pregnadiene 3,20 dione, there are prepared from the above procedure the following compounds respectively, 90,1 1 ddichlorod601-methy1-l701, 21 idopropylidenedioxy 21 methylene 1,4 pregnadiene 3,20 dione; 901,115 dichloro 16B methyl- 1701,21 isopropylidenedioxy 21 methylene 1,4 pregnadiene 3,20 dione; and 601 methyl 901,115 dichloro 1701,21 isopropylidenedioxy 21 methylenel,4-pregnadiene-3,20dione.

Substitution of other aldehydes in the above procedure results in the formation of the corresponding alkylidene derivatives. For example, by use of butyr-aldehyde, cyclohexyl acetaldehyde, and acetaldehyde, there are respectively prepared 901,111? dichloro 1701,21 isopropylidene 21 butylidene 1,4 pregnadiene 3,20 dione; 901,113 dichloro 1711,21 isopropylidene 21 (,6 cyclohexylethylidene) 1,4 pregnadiene 3,20 dione; and 901,115 dichloro 1701,21 isopropylidene 21 ethylidene-1,4-pregnadiene-3,20-dione.

EXAMPLE 28 9a,] Ifl-Dichloro-Z 701,21Jsopropylidenedioxy-Zl- Benzylidene-Z ,4-Pregnadiene-3,20-Dtime To a solution of 2 g. of 90.,11B-dichloro-17a,2l-isopropylidenedioxy-1,4pregnadiene-3,20-dione in 100 cc. of boiling methanol is added 1 g. of sodium imethoxide and 5 cc. of benzaldehyde. The solution is stirred overnight at 50 C. during which time the gradual precipitation of the crude product occurs. At the completion of the reaction period, there is added 125 cc. of water and the solid material present is collected by filtration and dried. Recrystallization from acetone-methanol yields 911,11 ,d-dichloro- 1711,21 isopropylidenedioxy 21 benzyiidene 1,4- pregnadiene-3,20-dione.

EXAMPLE 29 9a,]1B-Dichlor0-1 70,21-(2-Perztylidenediory) -.1,4- Pregnadiene-3,20-Di0ne The reaction procedure described in Example 1 is followed with the exception that 2,2-dimethoxypentane is EXAMPLE 30 901,11,B-Dichloro-lo-Methyiene-l 701,21-Ir0pr0pylidenedioxpJ,4-Pregrzadiene-3,20-Di0ne To a solution of 32 ml. of 50% aqueous sodium hydroxide in ml. of water is added 164 g. of 16-methyl- 5,16-pregnadiene-3B-ol-20-one previously dissolved in 500 ml. of chloroform and 1200 ml. of methanol. There is then added 225 ml. of 35% hydrogen peroxide While stirring and keeping the temperature below 25 C. Stirring is continued for 48 hours whereupon the mixture is acidified with acetic acid. There is then added a saturated solution of sodium sulfite suflicient to destroy excess peroxide as determined by an iodide-starch test. The mixture is then steam distilled and the oxide compound of Example 30A is removed by filtration. Purification is effected by recrystallization from acetone, M.P. 188 C.,

[01] 20 (1% in dioxane).

B. IGH-METHYL-IG,17-OXIDO-5PREGNENE-3fi-OL- 20-ONE 3ACE1TATE To a solution of 167 g. of the compound of Example 30A in 500 ml. of pyridine is added 170 ml. of acetic anhydride. The mixture is stirred at 60 C. overnight. The mixture is then cooled, 3 liters of water LBIS added and the mixture is filtered to yield the acetate compound which is purified by recrystallization from acetone, M.P. -182 C., [01] -I6.7 (1% in dioxane).

C. 16METEYLENE5-PREGNENE-3/3,17a-DIOIr20-ONE 3-ACETATE To a solution of 110 g. of the compound of Example 303 in 2.4 liters of acetic acid is added 2.5 g. of hydrogen bromide. The mixture is stirred at 30 C. for a few minutes. The precipitate is removed by filtration, washed with aqueous acetic acid and dried to yield 16-methylene- S-pregnene-Zvfi,17o1-diol-20-one 3-acetate, M.P. 200 C., [11] 109.5 (1% in dioxane).

D. 1G-METHYLENEJi-PREGNENE-3fl,1711,21 'IRIOL-20- ONE 3,21-DIACETATE To a solution of 10 g. of the compound of Example 300 in 230 ml. of methylene chloride and 600 ml. of acetic acid, which has been cooled to 5 C., is added with stirring a solution of 4.54 g. of bromine in 75 ml. of acetic acid over a ten minute period. There is then added 2 ml. of a 25% solution of hydrogen bromide in acetic acid followed by the dropwise addition of 4.54 g. of bromine in 75 ml. of acetic acid. After one-half hour, the bromination is completed and the methylene chloride removed by vacuum concentration at 30 C. The acetic acid solution is poured into water thus precipitating the crude 5,6,2l-tribromo substituted product.

The tribromo intermediate is dried in vacuo and dissolved in 600 ml. of acetone. There is added 20 g. of pulverized sodium iodide and the mixture is shaken vigorously for 30 minutes at room temperature. There is then added 80 g. of finely ground potassium acetate and the mixture is stirred and refluxed for 6 hours. After this eriod, the mixture is concentrated to one-half volume, poured into water and extracted four times with chloroform. The chloroform solution is shaken twice with water, dried and concentrated to a residue. The residue is purified by recrystallization from acetone, yielding 16- methylene-5-pregnene-3B,171:1,2l-triol 20-one 3,2l-diace tate, MP. 1'97 C., [01] 6S.7 (chloroform).

To a sterile nutrient solution of 36 g. of glucose, 9 g. yeast extract, 12 g. ammonium chloride, 6 g. magnesium sulfate heptahydrate, 21 g. disodium hydrogen phosphate is added an inoculum (800 ml.) of a strongly growing culture of Flavobacterium dehydrogenans var. lzydrolyticum (Waksman Collection No. 130). The growth culture is subjected to aeration (800 liters/minute) until there is attained an 80% increase in growth of the organism. There is then added 15 g. of the compound of Example 10D in 50 ml. of dimethylformamide. The formation of the 3-keto-A -system is followed hourly by examination of the U.V. absorption of a test sample (absorption A at 240 me). When optimum transformation has taken place, the broth is extracted four times with 15 liters of chloroform each. The chloroform extracts are combined and evaporated to a residue, the residue is purified by crystallization from acetone, M.P. 207 C., [u] -]-47.5 (chloroform) yielding 16 methylene-4- pregnene-17a,21-diol-3,20-dione.

F. l6-METHYLENE HYDROCO RTISONE To 15 liters of growth medium consisting of 3% glucose, 1% malt extract, 0.1% yeast extract, 0.2% sodium nitrate, 0.1% potassium dehydrogen phosphate, 0.05% magnesium sulfate heptahydrate and 0.01% ferrous sulfate heptahydrate is added an inoculum of 800 ml. of a culture of Curvularia lunate (N.R.R.L. 2380). Growth is permitted to occur at 28 C. while stirring and aerating for 18 hours. There is added g. of 16-methy1ene-4- pregnene-17u,21-diol-3,20-dione (from Example E) when the pH is determined to be about 6.5. Fermentation is continued for 1830 hours, the course of the reaction determined by paper chromatography. The fermentation broth is processed as in Example 10E. There is obtained 16-rnethylene hydrocortisone, M.P. 224-225 C., [a] +69.2 (dioxane) after recrystallization from acetone.

G. 1G-METHYLENEPREDNISOLO NE Bacillus sphaericus (A.T.C.C. 7055) is incubated on a nutrient agar (composed of bacto-oeef extract, 3 g.; bacto-peptone, 5 g.; sodium chloride, 8 g.; agar g.; tap water, 1 liter) for 24 hours at 28 C. To 5 liters of a sterile nutrient broth (composed of bacto-beef extract, 3 g.; bacto-peptone, 5 g.; per liter of tap water) is added 400 m1. of the shake culture prepared above and the broth mixture is further incubated for 7 hours. There is then asceptically added 1.1 g. of 16-methylene hydrocortisone and fermentation is permitted to occur for an additional 16 hours. The reaction broth is shaken with chloroform and the chloroform extract is steam distilled. The residue is purified by crystallization from acetone yielding 16-methylene-prednisolone, M.P. 210-211 C.

H. 1G-HETHYLENEPREDNISOLONE 2l-ACETATE To a solution of 0.9 g. of 16-methyleneprednisolone in 5 ml. of pyridine is added 3 ml. of acetic anhydride. The reaction mixture is allowed to stand at room temperature overnight, then is diluted with ice-water. The resulting precipitate is removed by filtration and recrystallized from acetone-hexane yielding l-methyleneprednisolone 21-acetate.

I. 16-ME'IHYLENE HYDROCORTISONE ZI-ACETATE By following the procedure of Example 30H, but employing 16-methylene hydrocortisone as the starting reactant, there is obtained 16-Inethylene hydrocortisone 21- acetate.

This substance, when subjected to the dehydrogenation of Bacillus sphaericus as described in Example 306 gives rise to the formation of 16-methyleneprednisolone 21- acetate, the compound of Example 30H.

.T. lti-llIETHYLENE-IAQ (11)-PREGNATRIENE-1'M,21- DIOL-3,20-DIONE ZI-ACETA' IE To a solution of 1 g. of 16-methyleneprednisolone 21- acetate in 15 ml. of anhydrous pyridine at 0 C. is added 1 g. of p-toluenesulfonyl chloride. The reaction mixture is allowed to warm to room temperature and stand overnight. The mixture is then diluted with water and the precipitate removed by filtration and dried. 16-methylene-1,4,9(11)-pregnatriene 17a,21-diol 3,20-dione 21- acetate is obtained from crystallization of acetone-hexane.

A solution of 1.0 g. of 16-methylene-1,4,9(11)-pregnatriene-17a,21-diol-3,20-dione 21-acetate and 5.0 g. of lithium chloride in 40 ml. of glacial acetic acid is treated with 0.410 g. of N-chlorsuccinimide, followed by 0.104 g. of anhydrous hydrogen chloride dissolved in 2.5 ml. of tetrahydrofuran. The reaction mixture is stirred for 2 hours and poured into ice-water. The crude product is filtered and washed with Water to give 1.12 g. of solid material, which is recrystallized from acetone-hexane to give substantially pure 9a,1lfi-dichloro-16-methylene-1,4- pregnadiene-17u,21-diol-3,20-dione 21-acetate.

L. 9a,1lfl-DICHLORO-lG-METHYLENE-l,4-PREGNA DIENE-l7a,21-DIOL-3,20-DIONE One gram of 9a,11fi dichloro-16-methylene-1,4-pregnadiene-17rx,21-diol-3,20-dione 21-acetate is refluxed in 10 ml. of methanol containing 0.22 g. of sodium bicarbonate and 1 ml. of water for 10 minutes. The mixture is then neutralized with acetic acid and the solvents removed in vacuo. Extraction of the residue and concentration of the extracts followed by recrystallization from hexane yields 904,1lfl-diChlO1O-16 methylene 1,4-pregnadiene-17o,21- dio1-3,20-dione.

M. 9a,11 3DICHLORO-1eMETHYLENE-He,21-ISOPRO- PYLIDENE-DIOXY-1,4-PREGNADIENE-EsQO-DIONE The compound prepared in part L of this example, 9:1,115 dichloro 16 methylene 1,4 pregnadiene- 17u,2l-di0l-3,20-di01'16 is subjected to the reaction procedure as described in Example 23. There is thus prepared upon purification in the manner therein described, the compound of this example, 901,11,8-dichloro-16-methylene 1704,21 isopropylidenedioxy 1,4 pregnadiene- 3,20-dione.

In a similar fashion, by following the procedure outlined in Example 30 parts A through M but omitting part G, there is prepared 9a,1lfi-dichloro-16-methylene- 17c,21-isopropylidenedioxy-4-pregnene-3,20-dione.

EXAMPLE 31 Qa-Brom 0-1 IB-FluOrO-I :,21Jsopropylidenedioxy-ZZ- Acetyl-I ,4 -Pregnadienc-3 ,20-D i one into water. The water mixture is next extracted with chloroform, dried over sodium sulfate and reduced to a residue. Upon recrystallization of the residue from acetone, there is obtained 9a-bromo-l1B-fluoro-17a,21- isopropylidenedioxy 21 acetyl 1,4 pregnadiene- 3,20-dione.

EXAMPLE 32 9ot-Br0m0-J 7 ot,21 Jsopropylidene ioxy-l ,4 -Pregizadiene- 11,8-Ol-3,20-Di0ne 1 JB-Acetate To a solution of 2.0 g. of 9or-bromo-1,4-pregnadiene- 11,8,l7a,21-triol-3,20-dione llfl-acetate in 4 ml. of di- EXAMPLE 33 9ot-Chl0r0-1 7:1,21-Is0pr0pylidenedioxy-1,4-Pregnadiene- 1J,8-Ol-3,20-Di0ne lIfi-Formate A. 9a-CHLORO-l,4-PREGNADIENE-11B,170.,21-TRIOL 3,20DIONE llfi-FORMATE One gram of 9a-chloro-1,4-pregnadiene-l1,8,17a,2ltriol-3,20-dione-11,8-frmate 2l-acetate is suspended in 60 ml. of 0.27 N methanolic perchloric acid and the suspension is stirred for 17 hours at room temperature. Four hundred ml. of water are then added and the resulting mixture filtered. The solid thus collected is dried and recrystallized from acetone-hexane to yield 9ocChlOr0- 1,4 pregnadiene 11,8,l7u,21 triol 3,20 dione 11,8- formate.

B. 9a-CHLORO-l7a,21-ISOPROPYLIDENEDIOXY-1,4- PREGNADIENE11fl-OL-3,20-DIONE llfi-FORMATE The compound prepared in part A of this example is subjected to the reaction procedure as described in Example 32. There is thus prepared upon purification in the prescribed manner, 9u-cl11oro-17u,2l-isopropylidene dioxy-1,4-pregnadiene-11/3-ol-3,20-dione llfi-formate.

EXAMPLE 34 90c chloro 1,4 pregnadiene 11B 17o,21 triol- 3,20-dione 11,21-diacetate is substituted for 9oc-ChlOrO-1,4 pregnadiene 11B,l70c,21 triol 3,20 dione 11f)- formate 21-acetate in Example 33 and upon execution of the procedure therein described there is obtained the compound 9a chloro 17a,21 isopropylidenedioxy- 1,4-pregnadiene-1 1 fi-o1-3,20-dione 11 ,B-acetate.

EXAMPLE 35 9a-ChIor0-1 6 a-M ethyl-1 704,21-Is0pr0pylidencdi0xyl,4-Pregnadiene-11,8-Ol-3,20-Di0ne 1 1 B-Formate A. QwCHLORO-lSat-METHYL-l,4-PZREGNADIENE-115,1771, 21-TRIOL-3,20-DIONE-l1H-FOR1\IATE ZLACETATE To a stirred solution of 1.0 g. of l6et-methyl-1,4,9(11)- pregnatriene-17a,21-diol-3,20-dione 21-acetate in 40 ml. of formic acid containing 4.0 g. of sodium formate are added 382 mg. of N-chlorosuccinimide followed immediately by 2.7 m1. of l N hydrochloric acid. The mixture is stirred for 3 hours at room temperature and then poured into 400 ml. of water. The solid is then collected by filtration, washed with Water, dried, and crystallized from acetone to yield 9u-chloro-l6a-methyl- 1,4 pregnadiene 11,8,17a,2l triol 3,20 dione 1l,8- formate 2l-acetate.

B. Qa-CHLORO-l6ct-METHYL-l,4-PREGNADIENE-115,1711, 21-TRIOL-3,20-DIONE 11,BFORl\IATE The product formed in part A of this example is subjected to the hydrolysis procedure as described in part A of Example 33. There is thus prepared upon purification in the manner therein described, 9a-chloro-l6amethyl 1,4 pregnadiene 115,17a,21 triol 3,20- dione 11 fi-formate.

c. Sa-CHLORO-lfia-METHYL 1711,21 JSOPROPYLIDENE' DIOXY-l,4PREGNADIENE-l1fl-OL-3,20-DIONE lie-Fort MATE The compound prepared in part B of this example, chloro 16a methyl 1,4 pregnadiene 11B,l7oc,21- triol-3,20-dior1e llfi-formate, is treated with 2,2-dimethoxypropane in the manner described in Example 32 with the reaction time extended to 15 hours. Purifica' tion in the manner therein prescribed yields the compound of this example, 9a-chloro-16a-methyl-17ot,21-isopropylidenedioxy 1,4 pregnadiene 11B ol 3,20- dione llfi-formate.

In a similar manner by starting with the 16,6-epimer, 16B methyl 1,4,9(11) pregnatriene 17a,21 diol- 3,20-dione 21-acetate and following the procedure in parts A, B and C of this example there is formed 90:- chloro 16,8 methyl 1711,21 isopropylidenedioxy- 1,4-pregnadiene-11;8-ol-3,20-dione 11,8-formate.

Likewise the higher alkyl analogs of the compound of this example are prepared by substitution of the appropriate l-alkyl-pregnatriene. There is thus prepared, 90a chloro 16cc ethyl 17a,2l isopropylidenedioxy- 1,4-pregnadiene-1 lfi-ol-3,20-dione llfi-formate.

EXAMPLE 36 9a-I0d0-1 7 06,21 -Cycl0hexyl idenedioxy-4-Pregnene- ]1{3-Ol-3,Z0-Dione l 1 fl-Acetate A. Qa-IODO--PREGNENEllfl,l7a,2l-TRIOL-3,20-DIONE 115,21-DIACETATE To a stirred solution of 5.0 g. of 4,9(ll)-pregnadiene- 17a,21-diol-3,20-dione 21-acetate in 200 ml. of glacial acetic acid is first added 20 g. of lithium acetate and then 3.3 g. of N-iodo-succinimide. The mixture is stirred for 17 hours at room temperature and then poured into 1000 ml. of water. The solid is collected by filtration, washed, dried, and crystallized from ethyl acetate to yield 90c iodo 4 pregnene 11,8,17ot,2l triol 3,20- dione llB,21-diacetate.

B. 9ct-IODO-4-PREGNENE-11B,17a,21-TRI0L-3,2 0-DIONE The product of part A of this example is treated with perchloric acid in the manner of Example 33A. There is obtained upon purification by the method therein described, 90L iodo 4 pregnene 1lfl,17oc,'21 triol 3,20 dione llfi-acetate.

C. 9a-IODO-1711,21 CYCLOHEXYLIDENEDIOXY- l-PREG- NENE-11fi-OL-3,20-DIONE llfl-ACETATE A solution of 2.0 g. of 9u-i0do-4-pregnene-115,111,21- triol-3,20-dione llfi-acetate in 4 cc. of dimethy-ltormamide and 15 .cc. of 1,1-dimeth0xycyclohexane to which a crystal of p-toluene-sulfonic acid has been added, is refluxed for 10 hours. The solvents are removed in vacuo and the residue chromatographed in the manner described in Example 32. There is thus prepared, 9ot-iodo-17a,21-cyclo hexylidenedioxy 4 pregnene 11p 01 3,20 dione 11 fl acetate.

EXAMPLE 37 9oc-Br0m0-1 7u,21- (3-Pentylidenedi0xy -1,4-Pregnadienel1fi-Ol-3,20-Dione 1 Ifl-Diethylacetate 9a-bromo-1,4-pregnadiene-11,B,17a,21 triol 3,20-dione llfi-diethylacetate is subjected to the reaction procedure of Example 32 with 3,3-dimethoxypentane substituted for 2,2-dimethoxypropane. There is thus obtained upon purification in the prescribed manner the compound, 9a-bIOInO-17oc,2 1- (3 -pentylidenedioxy l ,4 pregnadiene llfi-ol-3,20-dione llfi-diethylacetate.

EXAMPLE 38 To a stirred solution of 1.0 g. of 2-methyl-4,9(ll)- pregnadiene-17a,21-diol-3,20-dione 21-acetate in 200 ml. of tetrahydrofuran and 20 ml. of trifiuoroacetic acid is added 400 mg. of N-chloroacetamide. The temperature is maintained at 25 C. and stirring is continued for three hours. At the end of this time the mixture is poured into 400 ml. of water, filtered, dried, and recrystallized from acetone-hexane to yield 2-Inethyl-9a-chloro-4-pregnene- 1 1 ,8,17a,21-triol-3,20-dione 1 1 ,B-trifluoroacetate 2l-acetate.

This compound is then selectively hydrolyzed in the manner of Example 33A to obtain the corresponding 21-alcohol, 2-methyl-9u-chloro-4 pregnene 11,8,17a,21- triol-3,20-dione llfi-trifluoroacetate.

This compound is then subjected to the reaction procedure described in Example 32 with the exception that 2,2-dimethoxybutane is substituted for 2,2-dimethoxypropane. There is thus prepared the compound of this example, 2-methyl-9a-chloro-1711,21-(2-butylidenedioxy)- 4-pregnene-1 l,8-l-3,20-di0ne 11 fi-trifluoroacetate.

EXAMPLE 39 90t-ClZlOl0-1 7 oc,2] -I sopropy lidenedioxy-Zl -Methylene- 1,4-Pregnadiene-11/3-Ol-3,20-Di0ne JIB-Formate A. 17a,ZLISOPROPYLIDENEDIOXY-1,4,9 (11) -PREGNA- TRIENE-3,20DIONE This intermediate is prepared as in Example 18.

B. 2l-METHYLENE-1,4,9 (11) -PREGNATRIENE-17a, 21-DIOL-3,20DIONE ZI-ACETATE To a solution of 3.0 g. of 1711,21-isopropylidenedioxy- 1,4,9(11)-pregnatriene3,20-dione in 120 ml. of ethanol are added 750 mg. of sodium bicarbonate and 30 ml. of 37% formaldehyde solution. The mixture is then heated at 65-70 C. with stirring for a period of 16 hours, and at the end of this time water is added and the ethanol removed in vacuo. The mixture is next filtered and the solid thus collected Washed well with water.

This material is then added without further purification to 30 ml. of 50% acetic acid, and the mixture is heated at steam bath temperatures under a nitrogen atmosphere for 2 hours. The mixture is then concentrated to dryness in vacuo and the residue crystallized from acetone to yield 21-methylene 1,4,9(11) pregnatriene 170:,2l-di0l- 3,20-dione.

This material, 21-methylene 1,4,9(11) pregnatrienel7ot,21-di0l-3,20-dione, is dissolved in 1 m1. of pyridine and to the mixture is added 1 ml. of acetic anhydride. The mixture is allowed to stand overnight, and the solids are then removed in vacuo and the residue recrystallized from acetone-hexane to yield 21-methylene-1,4,9(11)- pregnatriene-17ot,21-diol-3,20-dione 21-acetate.

C. 9a-CHLORO-2l-METHYLENE-l,4-PREGNADIENE-11B, 17u,21TRIOL-3,20-DIONE llfi-FORMATE ZI-ACETATE By subjecting the compound prepared in part B of this example, 21-methylene-1,4,9( ll) pregnatriene 17a,2ldiol-3,20 dione 2l-acetate, to the reaction procedure as described in Example 35A, there is prepared upon purification as therein described 9a-chloro-21-methylene-1,4- pregnadiene-l1,8,l7m,2l-triol-3,20-dione llfi-formate 21- acetate.

D. 9a-CHLORO-2l-METHYLENE-l,4-PREGNADIENE- 11/3,17a,21-TRIOL-3,20-DIONE llfi-FORMATE The compound prepared in part C of this example is subjected to the selective hydrolysis procedure as set forth in Example 353, and there is thus formed 9a-chloro- 2l-metl1ylene 1,4 pregnadiene 11fl,17a,21 triol 3,20- dione lLB-formate.

E. 9a-CHLORO-17a,21-ISOPROPYLIDENEDIOXY-21-METH- MATE The product of part D of this example, 9a-chloro-21- methylene 1,4,9(1l) pregnatriene 11B,l7oc,21 triol- 3,20-dione 11/3-formate, is treated with 2,2-dimethoxypropane in the manner described in Example 32. Upon 24 purification in the manner therein described, there is obtained the compound of this example, 9oc-chl0IO-l7a,2lisopropylidenedioxy-21-methylene-1,4 pregnadiene 11 ol-3,20-dione 11,6-formate.

EXAMPLE 4O To a solution of 700 mg. of potassium in 50 ml. t-butanol, is added 1.0 g. of 17a,21-isopropylidenedioxy- 1,4,9(l1)-pregnatriene 3,20 dione. After solution has occurred there is added 15' ml. of methyl iodide, and the solution is refluxed under an atmosphere of nitrogen for 2 hours. At the end of this time the mixture is poured into water and extracted with chloroform, the chloroform extracts being dried over sodium sulfate and then concentrated to a residue in vacuo. The residue is then crystallized from acetone to yield 17a,21-isopropylidene clioxy-21-methyl-1,4,9 11)-pregnatriene-3,20-dione. The alkylidenedioxy group is then cleaved and the resulting free diol esterified according to the procedure described in Example 393. The remaining procedure described in Example 39, parts CE is then followed as therein described and there is thus prepared the compound of this example, 9a chloro 17a,2l isopropylidenedioxy 21- methyl-1,4-pregnadiene-1 1 fl-ol-3,20'-dione 1 lp-formate.

EXAMPLE 41 906-6111010-1 6 a,2 1 -D z'methyl-J 70:,21 -ls0pr0py lidenea'ioxy- 1,4-Pregnadiene-1IB-Ol-3,20-Di0ne 1 lfl-Formate A. 1(ia-METHYL-17a,21-ISOPROPYLIDENEDIOXY- 1,4,9 (11 PRE GNAIRIENE-3,20-DIO NE Following the procedure as described in Example 32 with 16a-methyl-1,4,9(11)-pregnatriene-17a,21-diol-3,20 dione being substituted for the steroid therein employed as the starting material and by extending the reaction period to 15 hours, there is prepared upon purification in the prescribed manner, l6a-methyl-17a,2l-isopropylidenedioxy-1,4,9(11)-pregnatriene-3,20-dione.

B. Qa-CHLORO 16:1,21 DIMETHYL-l'fa,ZI-ISOPROPYLI- DENEDIOXY 1,4 PREGNADIENE 11/3-OL-3,20-DIONE llfl-FORMATE The compound prepared in part A of this example, 16oc-methyl-17a,2l-isopropylidenedioxy 1,4,9(11) pregnatriene-3,20-dione, is subjected to the reaction procedure as described in Example 9, and there is thus formed the compound of this example, 9a-chloro-16a,21-dimethyl l7x,21-isopropylidenedioxy-1,4-pregnadiene-l 1,8 Ol-3,20- dione llti-formate.

EXAMPLE 42 fl-Ch lore-1 701,21 -Isopr0pylidenedi0xy-J 6 -M ethylene- I ,4-Pregnadiene-1 1B-Ol-3,20-Di0ne 1 lfl-Formate One gram of 16-methylene-1,4,9(1l)-pregnatrienel7u,2l-diol-3,20-dione 21-acetate is treated with formic acid, sodium formate, and N-chloro-succinimide according to the procedure of Example 35A. The compound obtained upon purification is next subjected to the procedures described in parts B and C of Example 35 and there is thus prepared upon purification in the prescribed manner, the compound of this example, 9ocChlOI0-17uc,2lisopropylidenedioxy-l6-methylene-1,4 pregnadiene 11/3- ol3,20-dione ll/i-formate.

EXAMPLE 43 6 a,21 -Dimethyl-9 u-Brom 0-] 711,21 Jsopropylz'denedioxy-4- Pregnene-I1B-Ol3,20-Dione II/i-Propionaze A. 6a-METHYL-17a,21-IS OPROPYLIDENEDIOXY- 4,9 (11 -PREGNA'DIENE-3,20-DION E Five grams of 60-I1'1thyl-4,9( 11)-pregnadiene-17a,21- diol-3,2'0-dione are dissolved in 10 ml. of dimethylformamide and 35 ml. of 2,2-dimethoxypropane, and to the resultant solution is added a crystal of p-toluenesulfonic acid. The mixture is refluxed for six hours, the solvents then removed in vacuo and the residue dissolved in benzene. The benzene solution is then placed upon a chromatographic-column comprising 100 g. of alumina and eluted with benzene followed by a 33% chloroform in benzene solution. The material which is first eluted is recrystallized from acetone to yield 6a-methyl-l7a,2lisopropylidenedioxy-4,9(11)-pregnadiene-3 ,20-dione.

B. 6a,21-DIMETHYL-17a,21'ISOPROPYLIDENEDIOXY- 4,9 11 runounmnnnaaomonn C. 6a.,21-DIMETHYL-9a-BROMO-17a,21-ISOPROPYLIDENE- DIOXY 4 PREGNENE-l1fi-OIx-3,20-DIONE llfl-PROPIO- NATE One gram of 6a, 2 l-dimethyl-l7u,2l-isopropylidenedioxy-4,9(11)-pregnadiene-3,20-dione is dissolved in 50 ml.

of propionic acid to which has been added 5 g. of sodium propionate, and there is then added 385 mg. of N-brornoacetamide. The mixture is stirred forfour hours and then poured into 400 ml. of-water. The solid thus formed is collected by filtration, washed well with water and dried.

The dried crude product thus obtained is treated without further purification with 2 ml. of dimethylformamide, 15 ml. of -2,2-dimethoxypropane and a crystal of p-toluenesulfonic acid. The mixture is treated according to the procedure of Example 32 and there is thus prepared upon purification in the prescribed manner, 6a,2l-dimethyl 9a bromo 170;,21 isopropylidenedioxy-4-pregnene-l 1,8-ol-3 ,20-dione 11 fl-propionate.

The following compounds are subjected to the above procedure:

6a-methyl-l,4,'9(l1)-pregnatriene-l7a,2l-diol-3 ,20-dione, 6 fl-methyl- 1,4,9 11)-pregnatriene-17ot,2l-diol-3,20-dione,

6a-fluoro-4,9( l 1)-pregnadienc-l7a,21-diol-3,20-dione and 6rx-flI1OI0-l,4,9 l l -pregnatriene-l7a,2l-diol-3 ,20-dione.

There are thus prepared:

611,21dimethyl-9a-brorno-17a,21-isopropylidenedioxy-1,4-

pregnadiene-l 1,8-01-3 ,ZO-dione llfl-propionate,

6 0,2 l -dimethyl-9 cz-bIOIHO- l 7x,2 l-isopropylidenedioxy-l ,4-

pregnadiene-l 1,8-01-3 ,20-dione-l 1 fi-propionate,

6a-fiuoro-9a-bromo-1711,21-isopropylidenedioxy2 l-methyl-4-pregnene-l 1fl-ol-3,20-dione 1 lfi-propionate, and

In a similar fashion by omitting. part B of this example but following parts A and C, there are prepared from the above recited starting materials, the compounds:

26 EXAMPLE 44 ZI-(LZ-Ethylene) -Prednis0l0ne 1704,21-A cetom'de To a solution of 1.46 g. of 21-methyleneprednisolonel7m,21-acetonide in 50 ml. of dry tetrahydrofuran was added a dry ethereal solution of diazomethane, prepared from 6.0 g. of nitrosomethylurea in the standard fashion. The solution was allowed to stand for 60 hours at 0-5 C. The solvent was removed at reduced pressure and the crystalline residue was recrystallized from acetone to afford 885 mg. of 2l-(1,2-ethylene)-prednisolone l7oc,21 acetonide, M.P. 242-.249. Further recrystallizations from acetone yielded the analytical sample, M.P. 248- 250;

X232 241 m te 17,800

AnaL-Calcd. for C23H34051 C, Found: C, 73.08; H, 7.92.

EXAMPLE 45 21 (1 ,Z-Ethylene -Prednis0l0ne my, 241 m (15,000) my, 2.8, 2.98, 5.82, 6.00, 6.16m

EXAMPLE 46 ZI-(LZ-EthyIene) Dexamethasone-Ihj]-Acet0nide To a solution of 450 mg. of ZI-methylene dexametha- =s0ne-17a,2l-acetonide in 10 ml. of tetrahydrofuran was added a dry ethereal solution (30 ml;) of diazomethane,

prepared in the usual manner from 1.5 g. of nitrosomethylurea. The solution was allowed to stand for 40 "hours at room temperature. The solution was evaporated to dryness under reduced pressure and the residue crystallized from acetone to yield 263 mg. of 21-(l,2-ethylene) dexamethasone-l7u,21-acetonide, M.P. 295300. The analytical sample was prepared by three recrystallizations from acetone, M.P. 301303 (dec.), [a] (CHCl )+19;

A252 3 my, e=17,000

AnaL-Calcd. for C H O F: C, 70.4; H, 7.60. Found: C, 70.23; H, 7.44.

EXAMPLE 47 21-(1,2-Ethylene) Dexamethasone A solution of mg. of 21-(1,2-ethylene) dexamethasone-l7m,21-acetonide in 20 ml. of 60% aqueous acetic acid is heated on a steam bath under a nitrogen atmosphere for .2 hours. The solution is then concentrated in vacuo and the residue chromatographed on a Chromosorb W (Iohns-Manville) partition column using a propylene glycol-toluene system to yield 2l-(l,2-ethylene) dexamethasone.

In a manner analogous to Examples 44 and 46 other 21-(1,2-ethylene) steroidal 17a,2l-acetonides may be produced which in turn when treated in a manner analogous to that of Examples 45 and 47 will yield the corresponding 21-(1,2-ethylene) steroidal compounds.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are Within the purview of the annexed claims, they are to be considered as part of this invention.

' 27 I claim:

1. A compound of the group consisting of pregnadienes having one of the structural formulae:

and the 1,2-dihydro analogs thereof, wherein Z is a member of the group consisting of H (H, lower alkyl), (H, lower alkanoyl), lower alkylene, lower alkyliclene, benzylidene, and cyclohexyl lower alkyl idene, R is a member of the group consisting of H and lower alkyl and R is a member of the group consisting of lower alkyl, phenyl, phenyl-lower alkyl, and that group which is formed by R and R together with the carbon atom to which both are attached consisting of cyclohexylidene and cyclopentylidene, A is a member of the group consisting of hydrogen and methyl, B is a member of the 3 5.3 6. The compound having the structural formula:

H2COH2 7. The compound having the structural formula:

H2C0H 8. 9a,11,B-dihalogeno 16 methyl-17a,21-lower alkylidenedioxy-1,4-pregnadiene-3,ZO-dione.

9. 9u,11fi-dichloro 16a methyl ;,21 ispropylidenedioxy-1,4-pregnadiene-3,20-dione.

10. 9a-11fi-di01110r0 16p methyl 17:1,21 isopropylidenedioxy-l,4-pregnadiene-3,2O-dione.

11. 9a-chloro 1701,21 isopropylidenedioxy-1,4-pregnadiene-l1,8-ol-3,20-dione llfi-formate.

12. 9u-chloro 16 methyl-471x31 isopropylidenedioxy-1,4-pregnadiene-11 8-ol-3,20-dione 11 fi-forrnate. v

13. The process which comprises treating a. 170L-21'dil1ydroxy-20-keto compound of the pregnane series with a reactant of the formula:

wherein R is a member of the group consisting of H and lower alkyl and R is a member of the group consisting of lower alkyl, phenyl, phenyl-lower alkyl, and that group which is formed by R and R together with the carbon atom to which both are attached consisting of cyclohexyliclene and cyclopentylidene, and P is a member of the group consisting of O and bis-lower alkoxy, in the presence of a strong acid, the acid being one having a log K of less than 2.25.

14. The process of claim 13, wherein the reaction is effected in an inert solvent at about the reflux temperature of the reaction mixture.

15. The process of claim 13, wherein the acid is ptoluenesulfonic acid.

16. The process of claim 14, wherein the reaction is effected in the presence of p-toluenesulfonic acid and the reactant is 2,2-bis-methoxypropane.

References Cited in the file of this patent Tanabe et a1. J.A.C.S. 83, 756757 (February 1961).

Gardi et a1. Tetrahedron Letters No. 13, pp. 448451 

1. A COMPOUND OF THE GROUP CONSISTING OF PREGNADIENES HAVING ONE OF THE STRUCTURAL FORMULAE: 